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Chemical Structure| 66493-39-8
Chemical Structure| 66493-39-8
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Product Details of [ 66493-39-8 ]

CAS No. :66493-39-8 MDL No. :MFCD00037428
Formula : C12H15NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :ZJDBQMWMDZEONW-UHFFFAOYSA-N
M.W : 237.25 Pubchem ID :2755931
Synonyms :

Calculated chemistry of [ 66493-39-8 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 63.65
TPSA : 75.63 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.83 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.22
Log Po/w (XLOGP3) : 2.7
Log Po/w (WLOGP) : 2.54
Log Po/w (MLOGP) : 1.97
Log Po/w (SILICOS-IT) : 1.14
Consensus Log Po/w : 2.11

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.94
Solubility : 0.27 mg/ml ; 0.00114 mol/l
Class : Soluble
Log S (Ali) : -3.94
Solubility : 0.0272 mg/ml ; 0.000114 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.73
Solubility : 0.443 mg/ml ; 0.00187 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.92

Safety of [ 66493-39-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 66493-39-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 66493-39-8 ]
  • Downstream synthetic route of [ 66493-39-8 ]

[ 66493-39-8 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 24424-99-5 ]
  • [ 150-13-0 ]
  • [ 66493-39-8 ]
YieldReaction ConditionsOperation in experiment
96% With sodium hydroxide In 1,4-dioxane; water at 20℃; for 24 h; To a mixture of 4-aminobenzoic acid 1a (5.00g, 36.5mmol) in dioxane (70mL) and water (35mL) were added NaOH (1.46g, 36.5mmol) followed by di-tert-butyl dicarbonate (11.9g, 54.8mmol). The reaction mixture was stirred at room temperature for 24h. Solvent was removed by rotary evaporation, and 3N aqueous hydrochloric acid was added dropwise to the residue to adjust pH 3. A precipitate was obtained, collected, washed with water, and dried to provide 2a (8.28g, 96percent) as a solid.
94%
Stage #1: at 20℃; for 0.0833333 h; Inert atmosphere
Stage #2: for 24 h; Inert atmosphere
4-(tert-butoxycarbonylamino)benzoic acid
4-Aminobenzoic acid (1.00 g, 7.29 mmol) was dissolved in 1,4-dioxane (15 mL) and H2O (7 mL). Et3N (2.0 mL, 14.58 mmol) was added to the solution and the reaction mixture was stirred for 5 minutes at room temperature. Di-tert-butyl dicarbonate (3.18 g, 14.58 m mol) was then added to the solution in one portion and the reaction mixture was stirred for 24 hours.
Following removal of the solvent in vacuo, 3M HCl was added to the residue yielding a white precipitate.
The slurry was then filtered and washed with H2O before drying in under high vacuum.
Recrystallization from hot methanol yielded the titled compound as a colorless solid (1.63 g, 6.85 mmol, 94percent yield).
mp: 192-194° C.
1H NMR (400 MHz, DMSO) δ 9.73 (s, 1H-CO2H), 7.83 (d, 2H, J=8.9 Hz), 7.55 (d, 2H, J=8.9 Hz), 1.47 (s, 9H) ppm.
13C NMR (100 MHz, CDCl3) δ 167.1, 152.6, 143.8, 130.4, 124.0, 117.2, 79.7, 28.1 ppm.
HRMS (ESI): Calculated for C12H15NnaO4 (M+Na)+: 260.0893. found: 260.0897.
93% With triethylamine In 1,4-dioxane; water at 23℃; for 48 h; 4-N-tert-Butoxycarbonylaminobenzoic Acid (7). To a solution of 4-aminobenzoic acid 6 (520 mg, 3.8 mmol) in dioxane/H2O (2:1) (13 mL) was added triethylamine (0.79 mL, 5.7 mmol) and Boc2O(1.31 mL, 5.7 mmol) at 23° C. and it was allowed to stir for 48 h at same temperature. The solvent was removed under reduced pressure, and 3 M HCl (5 mL) was added dropwise to the residue at 0° C. A precipitate was obtained, collected, washed with water, and dried to give corresponding acid 7 (836 mg, 93percent) as slightly yellow solid, Rf=0.78 (CH2Cl2:Me-OH=9:1). 1H NMR (400 MHz, CDCl3): δ 9.25 (brs, 1H), 7.91 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.7 Hz), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 169.7, 154.8, 131.8, 125.3, 118.6, 118.5, 81.3, 28.6. MS (Ei): m/z 237.10 [M]+. HRMS (EI), calcd for C12H15NO4 237.1001, found [M]+ 237.1004.
91.3% With triethylamine In methanol at 20℃; for 16 h; More specifically, Compound B-2 was obtained as follows. 4-amino benzoic acid (B-1) (2.00g, 14.6mmol) was dissolved in 140mL of methanol. Then, (Boc)2O (6.7mL, 29.1 mmol) and triethylamine (3.06mL, 21.9mmol) were added therein and stirred for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure, thereby obtaining a residue. Hexane and saturated sodium hydrogen carbonate aqueous solution (50mL) was added to the residue thereby performing extraction to obtain a water layer. The water layer was mixed with 10percent sodium citric acid aqueous solution until pH 4 was obtained, thereby precipitating out white solid. The thus obtained solid was dissolved in ethyl acetate and washed with water. The resultant was concentrated under reduced pressure. The residue from the concentration was recrystalized in ethyl acetate-hexane, thereby obtaining Compound B-2 (3.25g, Yield: 91.3percent) in the form of colorless crystals. 1H-NMR (270MHz, CD3OD) analysis of the thus obtained Compound B-2 showed that δ9.24 (1H, s, NH), 7.96 (2H, d, J = 8.9 Hz, aromatic), 7.55 (2H, d, J = 8.6 Hz, aromatic), 1.56 (9H, s, t-butyl). Moreover, ESI-MS (negative) analysis of Compound B-2 showed that m/z was 236.20 [(M-H)-]. These results confirmed the structure of Compound B-2. In addition, Compound B-2 was found to have a molecular mass of 237.25.
91% With triethylamine In 1,4-dioxane; water at 20℃; iert-Butyl 4-(qumolin-8-ylcarbamoyl)phenylcarbamate (45); A solution of 4-aminobenzoic acid (1.0 g, 7.3 mmol) and triethylamine (3.0 mL, 21.8 mmol) in l,4-dioxane H20 was treated di-iert-butyl carbonate (2.5 mL, 10.9 mmol) at room temperature overnight. After removing the solvent in vacuo, the residue was dissolved in EtOAc and washed with 1M HC1 solution. The organic phase was then extracted with 1M NaOH solution three times. The aqueous layer was then acidified by 1M HC1 solution and the precipitation was collected and washed with H20 to give 4-(fert-butoxycarbonylamino)benzoic acid (1.58 g, 91 percent). To a solution of 4-(rert-butoxycarbonylamino)benzoic acid (150 mg, 0.63 mmol) and pyridine (108 pL, 1.26 mmol) in C3/4C12 was added oxalyl chloride (57 pL, 0.63 mmol) at 0 °C for 15 min. 8-Aminoquiniline (90 mg, 0.63 mmol) was then added to the mixture. After kept at room temperature for lh, then reaction was quenched with MeOH and poured into H20 and extracted with CH2C12, dried over Na2S0 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (MeOH:CH2Cl2= 1:40 - 1:30) to give compound 45 (150 mg, 65 percent) NMR (300 MHz, CDC13) 610.72 (s, 1H), 8.95-8.87 (m, 2H), 8.21-8.04 (m, 4H), 7.63-7.47 (m, 4H), 6.82 (s, 1H), 1.55 (s, 9H); HR-MS Calcd. for (C2,H2iN303+H) 364.1661, found 364.1673.
90% With guanidine hydrochloride In ethanol at 35 - 40℃; for 2 h; General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
89% With triethylamine In 1,4-dioxane; water at 20℃; for 24 h; Triethylamine (0.4 ml, 3 mmol) followed by di-tert-butyldicarbonate (0.6 g, 3 mmol) is added to a mixture of 4-aminobenzoic acid (0.2 g, 1.5 mmol) in dioxane (4 ml) and H2O (2 ml). The reaction mixture is stirred at room temperature for 24 h. The solvent is removed at reduced pressure, and the residue is acidified with 1N HCl. The precipitate obtained is washed with H2O, obtaining I as a white solid (0.4 g, 89percent). 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H, COOH), 7.82 (d, J=8.7 Hz, H-2,6), 7.54 (d, J=9 Hz, H-3,5), 1.44 (s, 9H, 3CH3). 13C NMR (75 MHz, DMSO-d6) δ 167.4 (CO), 152.9 (CO), 144.1, 130.3 (2CHar), 124.4, 117.6 (2CHar), 80.0 (C(CH3)3), 28.4 (3CH3). HPLC gradient of 15-95percent CH3CN/H2O in 10 min, tr=4.25 min, m/z [M+H]+=237. Theoretical elemental analysis C12H15NO4: C, 60.75; H, 6.37; N, 5.90; experimental elemental analysis C, 60.84; H, 6.09; N, 5.95.
87% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; To a stirred solution of 4-aminobenzoic acid 6a (5.00 g, 36.5 mmol) and sodium hydroxide (1.56 g, 39.3 mmol) in 1:1 water/dioxane (60 mL) at 0 °C was added di-tert-butyl dicarbonate (14.3 g, 65.4 mmol). The resulting mixture was stirred for 3 h, then warmed to room temperature and stirred overnight. The aqueous mixture was then washed with ethyl acetate (60 mL) before further ethyl acetate (60 mL) was added and the resulting mixture neutralised with 1 M aqueous KHSO4. The organic layer was separated, washed with water (60 mL), dried (MgSO4) and the solvent removed in vacuo to give the title product 73a (7.53 g, 87percent) as an off-white solid, which was used without further purification. Mp 186-187 °C [lit.8 Mp 191-192 °C]; Rf=0.70 (CH2Cl2/MeOH=9:1); δH (400 MHz, DMSO-d6) 1.17 (9H, s, C(CH3)3), 7.23 (2H, d, J=8.6 Hz, Ar-H), 7.53 (2H, d, J=8.6 Hz, Ar-H), 9.38 (1H, s, NH). Spectroscopic data were in agreement with literature values.8
86% at 100℃; for 0.2 h; Microwave irradiation; Green chemistry General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)).#10;
86%
Stage #1: With triethylamine In 1,4-dioxane; water at 20℃; for 0.0833333 h;
Stage #2: at 20℃; for 26 h;
General procedure: To a solution of 12a (2.0 g, 14.6 mmol) in 67percent 1.4-dioxane/water(48 mL) was added triethylamine (4.07 mL, 29.2 mmol) at room temperature and allowed to stir for 5 min. Di-tert-butyl decarbonate(6.37 mL, 29.2 mmol) was then added to the solution. After beingstirred for 26 h, the reaction mixture was concentrated and acidified with 2M hydrochronic acid to yield a white precipitate. The slurry wasthen filtered, washed with water and dried over in vacuo to afford 13a(2.94 g, 86percent) as a white solid.4-((tert-Butoxycarbonyl)amino)benzoic acid (13a). Yield: 86percent.1H NMR (300 MHz, CDCl3)δ 8.03 (2H, dt, J=8.8, 2.1 Hz), 7.46 (2H, dt,J=8.9, 2.0 Hz), 6.71 (1H, s, H-N), 1.54 (9H, s, tBu-O).
79% With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; for 22 h; Step-1: To a solution of 4-aminobenzoic acid (5.0 g, 36.44 mmol) in 1,4-dioxan/10percent aq. NaHCO3 soln (1:1, 20 mL) was added a cat. amount of TBAB (0.58 g, 1.82 mmol) and the reaction mixture was stirred at 0° C. To it was added BOC anhydride (11.91 g, 54.6 mmol) and the reaction was allowed to stir at rt for 22 h. The reaction mixture was then acidified with 10percent aq. citric acid soln. when 4N-Boc-aminobenzoic acid precipitated out as a white solid. It was filtered, washed with water (100 mL), dried to get 4N-Boc-aminobenzoic acid (6.8 g, 79percent) as a white solid, which was used for next step.
72%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 20℃;
Stage #2: With hydrogenchloride In water
Commercially available 4-amino benzoic acid (5 g, 36 mmol) was dissolved in 1 M sodium hydroxide solution (40 mL, 40 mmol) and 1,4 dioxane (30 mL). After the addition of di-tert-butyl dicarbonate (7.85 g, 36 mmol), the mixture was stirred at room temperature over the weekend. The dioxane was removed in vacuo and the residue was diluted with water (100 mL). Then concentrated hydrochloric acid (37percent) was added until pH3. The precipitate was collected by filtration, washed with water (100 mL) and air-dried to afford the title compound as a white solid (6.3 g, 72percent).
71% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24 h; To a solution of 4-aminobenzoic acid (ig, 7.29mmol) in a mixture of dioxane:water (2OmL:lOmL) was added sodium hydroxide (2M, 35mL). The mixture was stirred until complete dissolution and then it was added di-tert-butyl dicarbonate (3.18g, 14.S7mmol) at 0°C. The reaction mixture was stirred 24 hours at room temperature. The solvent was removed under reduced pressure and the crude was acidified with hydrogen chloride SN. The precipitate obtained was filtered and washed with water to obtain the title compound as a white solid (1 .23g, 71percent).LRMS (mlz): 238 (M+1)+
69.4% With triethylamine In 1,4-dioxane; water at 0 - 20℃; for 48 h; STEP-5:Synthesis of compound 10
Procedure:To a solution of 4-amino benzoic acid (50 g, 364.9 mmol) and TEA (66.35g, 656.9 mmol) in 1,4-dioxane: H20 (1000 mL) was added (Boc)20 (89.2 g, 401.3 mmol) at 0°C and warmed to rt stirred for 48h at rt. The reaction mixture was diluted with water (250mL), adjusted the reaction mixture to acidic (PH~5) using saturated citric acid solution, then extracted the aq acidic solution with ethyl acetate (1000 mL), separated the organic layer washed with brine solution (100 mL), dried over anhydrous Na2S04 and evaporated under the reduced pressure. The crude product was triturated with 500 mL of hexane, filtered and dried under vacuum to yield 60 g (69.4 percent) of compound 4b as a half white solid.TLC system: Methanol: CHC13(1: 9) Rf value: 0.6
70.6% With sodium hydroxide In 1,4-dioxane A.
N-BOC-4-aminobenzoic acid
4-amino-benzoic acid (10 g, 72.9 mmol) was placed into a mixture of dioxane (145.8 ml) and 0.5M NaOH (145.8 ml).
The solution was cooled to 0° C. and di-t-butyl dicarbonate (23.87 g, 109.5 mmol) was added.
The reaction mixture was allowed to warm to room temperature and stirred overnight.
The next day, the dioxane was removed, the residue was made acidic and extracted into ethyl acetate.
The ethyl acetate fractions were combined and washed with 1N HCl to remove any unreacted starting material.
The solution was dried over Na2 SO4 and the solvent was removed in vacuo.
The crude material was recrystallized from ethyl acetate/hexanes to yield 12.2 g (70.6percent) of pure product. mp 189-190° C.; 1 H NMR (CD3 OD) 1.52 (9H, s), 7.49 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6 Hz), 9.28 (1H, s); 13 C NMR (CD3 OD) 28.59, 81.29, 118.54, 125.30, 131.81, 145.70, 155.00, 169.80; anal. calc. for C12 H15 NO4, C: 60.76, H: 6.37, N: 5.90; found, C: 60.52, H: 6.43, N: 5.83; HRMS calc. for C12 H15 NO4, 237.0961, found, 237.1001.
70.6% With sodium hydroxide In 1,4-dioxane N-BOC-4-aminobenzoic acid
4-amino-benzoic acid (10 g, 72.9 mmol) was placed into a mixture of dioxane (145.8 ml) and 0.5M NaOH (145.8 ml).
The solution was cooled to 0° C. and di-t-butyl dicarbonate (23.87 g, 109.5 mmol) was added.
The reaction mixture was allowed to warm to room temperature and stirred overnight.
The next day, the dioxane was removed, the residue was made acidic and extracted into ethyl acetate.
The ethyl acetate fractions were combined and washed with 1N HCl to remove any unreacted starting material.
The solution was dried over Na2 SO4 and the solvent was removed in vacuo.
The crude material was recrystallized from ethyl acetate/hexanes to yield 12.2 g (70.6percent) of pure product. mp 189°-190° C.; 1 H NMR (CD3 OD) 1. 52 (9 H,s), 7.49 (2 H, d, J=8.6 Hz), 7.91 (2 H, d, J=8.6 Hz), 9.28 (1 H, s); 13 C NMR (CD3 OD) 28.59, 81.29, 118.54, 125.30, 131.81, 145.70, 155.00, 169.80; anal. calc. for C12 H15 NO4, C: 60.76, H: 6.37, N: 5.90; found, C: 60.52, H: 6.43, N: 5.83; HRMS calc. for C12 H15 NO4, 237.0961, found, 237.1001.

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  • 2
  • [ 110969-44-3 ]
  • [ 66493-39-8 ]
YieldReaction ConditionsOperation in experiment
74.5% With water; sodium hydroxide In methanol at 25℃; A mixture of compound 8 (300mg, 1.l3mmol) and NaOH (1M, 7mL) in MeOH (5 mL) was stirred at room temperature for overnight. After concentrated, the residue was dissolved in H20, 1 N HC1 was added until pH=2, and the mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the product compound 9(200mg, yield: 74.5percent). It was used for the next step without further purification. ‘H NIVIR (DMSO-d6, 400MHz): 12.64 (s, 1H), 9.77 (s, 1H), 7.89(d, 2H, J = 8.4Hz), 7.61 (d, 2H, J = 8.8Hz), 1.54 (s, 9H).
38%
Stage #1: With lithium hydroxide; water In tetrahydrofuran; methanol at 20℃; for 16 h;
Stage #2: With hydrogenchloride In water
The ester prepared in preparation 24 (1.3 g, 4.90 mmol), lithium hydroxide (720 mg, 17.15 mmol), methanol (24.5 mL), water (24.5 mL), and tetrahydrofuran (73.5 mL), were combined in a 250 mL round bottomed flask, fitted with a stirbar, and under a nitrogen atmosphere. The mixture was stirred vigorously at room temperature for 16 hours, then concentrated under vacuum, dissolved in 1N HCl, and extracted with methylene chloride (100 mL*3). Organic layer was next dried (MgSO4), filtered, and concentrated under vacuum, yielding 1.07 g of white solid. This material was purified by silica gel chromatography, using a Chromatotron(R) with a 6000 uM rotor, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 440 mg (38percent) white solid.[0181] Electrospray-MS 238.0 (M*+1).
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  • 3
  • [ 124-38-9 ]
  • [ 66493-39-8 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 27, p. 8706 - 8707
  • 4
  • [ 24424-99-5 ]
  • [ 97364-15-3 ]
  • [ 66493-39-8 ]
YieldReaction ConditionsOperation in experiment
30%
Stage #1: With sodium azide; methanesulfonic acid; trifluoroacetic acid In hexane at 40℃; for 4 h; Sealed tube
General procedure: A 20 ml vial equipped with a magnetic stirring bar was charged with secondary alcohols (0.3 mmol, 1 equiv.), NaN3 (0.75 mmol, 2.5 equiv.), n-hexane (1.0 ml, 0.3 M) and TFA (5.4 mmol, 18 equiv.) or a mixture of TFA (3.6 mmol,12 equiv.) and MeSO3H (1.8 mmol, 6 equiv.). The vial was sealed and stirred under air at 40 °C for 4 h. On completion, the reaction mixture was quenched by 2 M NaOH (5 m), extracted by ethyl acetate (5 × 2 m) and the combined organic phase was washed with brine and dried over Na2SO4. Then the mixture was concentrated and purified by flash chromatography on a short silica gel column.
Reference: [1] Nature Chemistry, 2019, vol. 11, # 1, p. 71 - 77
  • 5
  • [ 144072-29-7 ]
  • [ 66493-39-8 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 4, p. 2647 - 2654
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